Clinical characteristics.

Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia.

Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare.

Wide clinical variability is observed among affected individuals, even within the same family.

Diagnosis/testing.

The clinical diagnosis of Alström syndrome is based on cardinal clinical features that emerge throughout infancy, childhood, and young adulthood. The molecular diagnosis of Alström syndrome is established in individuals of all ages by identification of biallelic pathogenic variants in ALMS1 on molecular genetic testing.

Management.

Treatment of manifestations: No therapy exists to prevent the progressive organ involvement of Alström syndrome. Individuals with Alström syndrome require coordinated multidisciplinary care to formulate management and therapeutic interventions. Red-orange tinted prescription lenses may reduce symptoms of photodysphoria; early educational planning should be based on the certainty of blindness. Obesity and insulin resistance are managed by a healthful, reduced-calorie diet with restricted simple carbohydrate intake and regular aerobic exercise. Myringotomy and/or hearing aids as needed for hearing impairment. Standard therapy for heart failure / cardiomyopathy. Standard treatment of insulin resistance / T2DM as in the general population. Consider nicotinic acid derivatives for hyperlipidemia; consultation with an endocrinologist if pubertal development and/or menses are abnormal; urinary diversion or self-catheterization in those with voiding difficulties; renal transplantation has been successful in a number of cases; appropriate therapy for portal hypertension and esophageal varices.

Surveillance: Routine assessment of vision and hearing; weight, height, and body mass index; heart (including echocardiography and EKG in all individuals, and MRI in those age >18 years); postprandial c-peptide and glucose and HbA1C starting at age four years; lipid profile; plasma ALT, AST, and GGT concentrations; thyroid function. Twice-yearly CBC, electrolytes, BUN, creatinine, cystatin-C, uric acid, urinalysis. Renal and bladder ultrasound examinations every one to two years if symptomatic and/or if urinalysis is abnormal.

Agents/circumstances to avoid: Any substance contraindicated in persons with renal, hepatic, and/or myocardial disease. Therapy directed at one system may have adverse effects on other systems; for example, the use of glitazone therapy in diabetes mellitus is contraindicated in the presence of cardiac failure.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with Alström syndrome in order to identify as early as possible those who would benefit from prompt evaluation for manifestations of Alström syndrome, initiation of treatment, and/or surveillance for age-related manifestations.

Genetic counseling.

Alström syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When the ALMS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Alström syndrome should be suspected in individuals with the following clinical findings that evolve as affected individuals age [Marshall et al 2005]:

• Cone-rod dystrophy with decreased vision and secondary nystagmus and photodysphoria (light sensitivity / photophobia) usually within the first year of life. Full-field electroretinography, required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels.
• Early childhood-onset obesity, primarily truncal with a body mass index (BMI: kg/m²) greater than 25 (for adults) or greater than the 95th centile on age- and sex-appropriate growth charts
• Progressive bilateral sensorineural hearing impairment (initially in the high-frequency range), usually diagnosed between ages one and ten years, although onset can vary
• Acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy
• Insulin resistance / type 2 diabetes mellitus (T2DM), the result of tissue resistance to the actions of insulin, usually present in childhood and manifest as elevated plasma insulin concentration and glucose intolerance. Insulin resistance ranges from hyperinsulinemia to glucose intolerance to T2DM, depending on the age of the individual. T2DM can develop in childhood or adolescence.
• Normal stature in childhood; short stature in adulthood
• Hypogonadism, non-autoimmune hypothyroidism, and female hyperandrogenism
• Urologic dysfunction / detrusor instability
• Progressive decrease in renal function
• Hepatic disease that is variable and ranges from elevated transaminases to steatohepatitis / nonalcoholic fatty liver disease (NAFLD). The liver and spleen may be enlarged. Extensive fibrosis, cirrhosis, portal hypertension, and liver failure have been described.
• Hypertriglyceridemia
• Hypertension
• Gradual thickening of subcutaneous tissues (e.g., thick ears)
• Alopecia

Establishing the Diagnosis

The clinical diagnosis of Alström syndrome is based on cardinal clinical features that emerge throughout infancy, childhood, and young adulthood (Table 1 and Figure 1); therefore, the accuracy of the proposed clinical diagnostic criteria is low in children before age five years, especially in the absence of infantile cardiomyopathy [Marshall et al 2013, Louw et al 2014, Khan et al 2015, Long et al 2015, Xu et al 2016, Nerakh & Ranganath 2019, Weiss et al 2019].

Figure 1.

Age range of onset of features in Alström syndrome

The molecular diagnosis of Alström syndrome is established in individuals of all ages by identification of biallelic pathogenic variants in ALMS1 on molecular genetic testing (see Table 2). Because atypical clinical presentations of Alström syndrome are increasingly recognized [Taşdemir et al 2013, Casey et al 2014, Sanyoura et al 2014, Bronson et al 2015, Yang et al 2017, Maltese et al 2018], molecular genetic testing is recommended in individuals with suggestive clinical features.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Alström syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Alström syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The first clinical manifestation of Alström syndrome (Table 3) is usually nystagmus caused by cone-rod dystrophy and/or infantile-onset cardiomyopathy. Later-onset findings include obesity that manifests during the first years of life, progressive sensorineural hearing loss (SNHL), insulin resistance / T2DM, adolescent- or adult-onset restrictive cardiomyopathy, hepatic steatosis, and progressive renal dysfunction. Wide clinical variability is observed among individuals with Alström syndrome, including among sibs [Hoffman et al 2005].

Cone-rod dystrophy. In most affected individuals, visual problems present as progressive cone dystrophy resulting in visual impairment, photophobia, and nystagmus between birth and age 15 months. Rod function is preserved initially but deteriorates as the individual ages, with visual acuity of 6/60 or less by age ten years, increasing constriction of visual fields, and no light perception by age 35 years [Nasser et al 2018].

Optical coherence tomography (OCT) reveals central macular changes that are mild during early childhood but slowly progress, resulting in loss of photoreceptors and retinal pigment epithelium. Severe retinal wrinkling, intraretinal opacities, foveal contour abnormalities, optic nerve drusen, vitreoretinal separation, and hyperreflectivities in all retinal layers are observed. The severity of the macular changes on OCT correlates with vision [Dotan et al 2017]. The severity and age of onset of the retinal degeneration vary among affected individuals [Malm et al 2008]. While many individuals lose all perception of light by the end of the second decade, a minority retain the ability to read large print into the third decade. Posterior subcapsular cataracts are common, even in the absence of diabetes.

Obesity. Children with Alström syndrome have normal birth weight. Hyperphagia and excessive weight gain begin during the first years, resulting in childhood obesity. In some individuals body weight tends to normalize, decreasing into the high-normal to normal range after adolescence.

Progressive bilateral SNHL presents in the first decade in as many as 70% of individuals with Alström syndrome; average age at detection of hearing loss is seven years [Marshall et al 2005, Ozantürk et al 2015, Lindsey et al 2017]. A majority of affected infants pass newborn screening for hearing loss [Lindsey et al 2017]. Hearing loss may be detected as early as age one year. Initially in the high frequency range, hearing loss may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade [Van den Abeele et al 2001].

In 33 individuals with Alström syndrome, the average rate of progression of hearing loss was 10-15 db/decade [Lindsey et al 2017]. The auditory defect in Alström syndrome is mapped to the outer hair cells of cochlea based on absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brain stem responses [Lindsey et al 2017]. Therefore, individuals with Alström syndrome are good candidates for aural amplification or cochlear implantation in cases of severe-to-profound hearing loss [Florentzson et al 2010, Lindsey et al 2017].

A high incidence of adhesive otitis media (glue ear) due to long-standing fluid in the middle ear can lead to an additional conductive hearing loss [Marshall et al 2005].

Cardiomyopathy. More than 60% of individuals with Alström syndrome develop congestive heart failure at some stage of their lives as a result of infantile-, adolescent-, or adult-onset cardiomyopathy. Onset, progression, and clinical outcome of cardiomyopathy can vary, even within families [Hoffman et al 2005, Mahamid et al 2013, Brofferio et al 2017].

More than 40% of infants with Alström syndrome present with a transient but severe cardiomyopathy with onset between ages three weeks and four months [Marshall et al 2005, Brofferio et al 2017]. Of note, the proportion of those with Alström syndrome who develop infantile-onset cardiomyopathy may be underestimated because some infants may succumb before the diagnosis of Alström syndrome [Louw et al 2014]. Most infants with severe cardiomyopathy develop irreversible heart failure, leading to death within the first weeks to months of life. Autopsy findings in these neonates show dramatically increased mitotic activity in the cardiomyocytes (i.e., mitogenic cardiomyopathy) [Louw et al 2014, Shenje et al 2014]. Most infants who survive make an apparently full recovery by age two years.

About 20% of individuals with Alström syndrome develop a later-onset progressive restrictive cardiomyopathy identified between the teens and late 30s. A characteristic feature of these individuals appears to be myocardial fibrosis documented at postmortem [Marshall et al 2005] and on cardiovascular MRI in asymptomatic and clinically affected individuals [Loudon et al 2009, Corbetti et al 2013, Edwards et al 2015]. Strain echocardiography suggests that some degree of myocardial fibrosis is probably present in almost all individuals with Alström syndrome including asymptomatic children [Brofferio et al 2017].

Flow-limiting coronary artery disease occurs in approximately 10% but does not appear to be related to progression of myocardial fibrosis.

Severe insulin resistance / type 2 diabetes mellitus (T2DM) are hallmarks of Alström syndrome. The age at which T2DM develops varies; it has been reported at as early as age five years. Insulin resistance proceeds to T2DM in the majority by the third decade. Insulin resistance results in the skin changes of acanthosis nigricans; i.e., velvety hyperpigmented patches in intertriginous areas [Akdeniz et al 2011, Han et al 2018]. An obesity-related contrast in the incidence of T2DM has been described in Canadian versus Italian cohort studies of children with Alström syndrome followed from childhood through to adolescence, with much lower diabetes rates in the leaner Italian children [Mokashi & Cummings 2011, Bettini et al 2012].

In a small study of 12 unrelated individuals with Alström syndrome, obesity (BMI and waist circumference) decreased with age, whereas insulin resistance increased with age [Minton et al 2006]. The hyperinsulinism was out of proportion to the degree of obesity. Consistently, in a recent study comparing 38 individuals with Alström syndrome to 76 age-, sex-, and BMI-matched controls, the severity of insulin resistance in individuals with Alström syndrome was documented to be more than five times that of equally obese controls [Han et al 2018], and metabolic syndrome (defined as ≥3 of the following: abdominal obesity, hypertriglyceridemia, low HDL-cholesterol, hypertension, impaired glucose tolerance) was ten times more common in Alström syndrome compared to controls.

Coronary artery disease as a result of insulin resistance, diabetes, dyslipidemia, and renal failure was reported in one affected individual [Jatti et al 2012]. A more recent cohort study of individuals from the UK has shown that duration of diabetes is linked with increased carotid-femoral pulse wave velocity and that this in turn predicts occurrence of atherosclerosis [Paisey et al 2015]. The authors' unpublished data show coronary artery disease to be increasingly common in adults with Alström syndrome (observed in up to 10%).

Diabetic peripheral neuropathy with risk of foot ulceration occurs rarely if at all in Alström syndrome [Paisey et al 2009] in contrast to patients with adolescent-onset T2DM without Alström syndrome, in whom 30% had severe peripheral neuropathy.

Hyperlipidemia. Insulin resistance is associated with hypertriglyceridemia in >90% of individuals with Alström syndrome [Paisey et al 2004, Paisey et al 2009, Han et al 2018]. Serum triglyceride levels commonly range from 2 to 5 mmol/L (177 to 443 mg/dL) with HDL cholesterol <1 mmol/L (39 mg/dL) and total cholesterol levels from 5 to 7 mmol/L (193 to 271 mg/dL). In some cases serum triglyceride levels can increase to well above 20 mmol/L (1,770 mg/dL). Affected individuals are at risk for sudden increase in triglycerides, precipitating life-threatening pancreatitis [Marshall et al 2005].

Short stature. Growth rates for young children are normal, but accelerated skeletal maturity (2-3 years advanced bone age) and low-serum growth hormone concentrations result in adult stature that is typically below the 25th centile. In about 98% of individuals older than age 16 years height is below the fifth centile [Maffei et al 2007].

Male pubertal development. A variable combination of hypogonadotropic hypogonadism and testicular fibrosis can result in delayed or arrested puberty in males, resulting in normal or immature secondary sexual characteristics; gynecomastia may be present [Marshall et al 2005]. Male fertility, which has not been systematically studied, has not been reported in males with biallelic ALMS1 pathogenic variants.

Female pubertal development. Endocrine disturbances in females include reduced plasma gonadotropin concentrations, hirsutism, polycystic ovarian syndrome associated with insulin resistance, precocious puberty, irregular menses, or amenorrhea. External genitalia are normal in females, though breast development is often poor.

Fertility in females has not been systematically studied. Although a molecular diagnosis was not confirmed, one clinical report describes two unrelated females with late presentation of the syndrome, each of whom had healthy children [Iannello et al 2004].

Urologic disorders of varying severity, which affect approximately 50% of affected individuals, can include detrusor-urethral dyssynergia (lack of coordination of bladder and urethral muscle activity). The greatest problems appear to occur in females in their late teens. Minor manifestations include urgency and long intervals between voiding, suggesting decreased bladder sensation, hesitancy, and poor urinary flow. Moderate manifestations include urinary frequency, incontinence, and symptoms associated with recurrent infections. More severe manifestations are rare (<2%) and include worsening urinary incontinence or retention; these symptoms may alternate. Lower abdominal and perineal pain is common and may relate to abnormal bladder/sphincter function [MacDermott 2001].

Renal disease is common, slowly progressive, and highly variable [Waldman et al 2018]. Onset can be in mid-childhood through adulthood. End-stage renal disease can occur as early as the mid- to late teens.

Renal ultrasonography and MRI may reveal abnormalities [Waldman et al 2018]. The most common ultrasonography finding is renal parenchymal hyperechogenicity often limited to the medulla. Renal cysts are identified in a small number of patients [Waldman et al 2018, Baig et al 2020].

Renal biopsy often shows interstitial fibrosis, glomerular hyalinosis, and tubular atrophy but absence of histopathologic features of diabetic or reflux nephropathy [Marshall et al 2005, Baig et al 2020]. In addition, glomerular function in Alström syndrome does not show significant association with T2DM, hyperlipidemia, cardiomyopathy, or hypertension, suggesting that kidney disease is a primary manifestation of the syndrome. Diabetes and hypertension may have an additive effect on the progression of renal disease.

Obstructive uropathy is rare.

Hepatic disease. Individuals with Alström syndrome have disproportionately high liver fat in comparison to equally obese controls [Han et al 2018]. Their risk of advanced NAFLD and cirrhosis is disproportionately increased for their age, BMI, and duration of diabetes [Gathercole et al 2016]. Plasma concentration of liver enzymes is often elevated starting in early childhood. Hepatomegaly is common. In some affected individuals liver disease progresses to cirrhosis and hepatic failure in the second to third decade. Portal hypertension associated with splenomegaly, esophageal varices, ascites, and hepatic encephalopathy may occur.

Liver biopsies and postmortem examination have revealed varying degrees of steatohepatitis, hepatic fibrosis, cirrhosis, chronic nonspecific active hepatitis with lymphocytic infiltration, and patchy necrosis [Quiros-Tejeira et al 2001, Marshall et al 2005]. Early stages of steatohepatitis can remit and relapse with significant improvements in exercise tolerance, insulin resistance, and blood sugar [Paisey et al 2014].

Gastrointestinal disease. General gastrointestinal disturbances such as epigastric pain and gastroesophageal reflux disease are common.

Pulmonary involvement ranges in severity from frequent upper and lower respiratory infections to pulmonary fibrosis and pulmonary hypertension. Recurrent upper and lower respiratory infections are common at all ages. Evaluation of pulmonary function is problematic because individuals with Alström syndrome have difficulty with deep inspiration / forced expiration. Most frequently there is restrictive lung disease due to kyphoscoliosis, sometimes in combination with pulmonary fibrosis, which has been confirmed in postmortem tissue. This may progress (with the added effects of cardiomyopathy) to pulmonary hypertension. The resulting susceptibility to severe hypoxia postoperatively or during episodes of pneumonia has been reported [Khoo et al 2009, Florentzson et al 2010].

A study of the burden of otosinopulmonary disease in 38 individuals with Alström syndrome revealed that recurrent otitis media was ubiquitous (92%), with 50% requiring pressure-equalization tube placement [Boerwinkle et al 2017]. A history of bronchitis/pneumonia and sinusitis was reported in 61% and 50% of individuals, respectively. However, manifestations of primary ciliary dyskinesia (PCD) (laterality defects, unexplained neonatal respiratory distress, year-round nasal congestion, and wet cough) were far less prevalent in individuals with Alström syndrome compared to those with PCD. In addition, the average nasal nitric oxide production in this cohort was 232 ± 57.1 nL/min compared to <77 nL/min required for a diagnosis of PCD.

Other findings include the following [Marshall et al 2005]:

• Scoliosis and kyphosis of varying severity (30%-70%) [Van den Abeele et al 2001] beginning in puberty [Maffei et al 2002]
• Severe flat feet (pes planus)
• Dental abnormalities
• Hypothyroidism (20%-30%) [Han et al 2018]
• Hypertension, often beginning in childhood (30%)
• Delay in early developmental milestones in ~20% of affected individuals, most commonly in gross and fine motor skills; ~30% have a learning disability. Cognitive impairment (IQ <70) is very rare.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are challenging because almost all ALMS1 pathogenic variants are null variants and the majority of affected individuals are compound heterozygous for rare variants reported in only a few families [Marshall et al 2015].

Prevalence

The prevalence of Alström syndrome is difficult to estimate; it is possible that individuals with attenuated forms of Alström syndrome may be underdiagnosed [Paisey et al 2011]. Estimates of the prevalence range from 1:100,000 [Minton et al 2006] to 1:1,000,000 [Marshall et al 2011b, Orphanet].

About 950 individuals diagnosed with Alström syndrome have been identified worldwide (Orphanet, accessed 4-8-19).

Ethnically or geographically isolated populations have a higher-than-average frequency of Alström syndrome [Deeble et al 2000, Ozantürk et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Alström syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

A suggested plan for annual evaluations for patients with Alström syndrome may be found at www.alstrom.org.uk [Paisey & Leeson-Beevers 2016].

Agents/Circumstances to Avoid

Substances contraindicated in persons with renal, hepatic, and/or myocardial disease should be avoided.

Therapy directed at one system may have adverse effects on other systems; for example, the use of glitazone therapy in diabetes mellitus is contraindicated in the presence of cardiac failure.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with Alström syndrome in order to identify as early as possible those who would benefit from prompt evaluation for manifestations of Alström syndrome (Table 5), initiation of treatment, or surveillance for age-related manifestations (Table 6).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A treatment trial with the antifibrotic agent PBI-4050 is currently under way [Baig et al 2018].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Alström syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one ALMS1 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. No males with molecularly confirmed Alström syndrome are known to have fathered children and no females are known to have become pregnant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ALMS1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ALMS1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the ALMS1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ALMS1 encodes ALMS1, a large (>4,000-amino acid) protein that localizes to the proximal ends of centrioles / basal bodies as well as non-centrosomal sites. Consistent with the complexity of the clinical features of Alström syndrome, ALMS1 appears to have multiple functions. Although the precise functions of ALMS1 are not fully understood, evidence suggests that it is implicated in formation and maintenance of primary cilia but also has non-ciliary functions including actin organization and endosomal trafficking. The mitotic nature of the infantile-onset cardiomyopathy in Alström syndrome demonstrates the importance of ALMS1 in cell cycle regulation in perinatal cardiomyocytes. Similarly, consistent with the severe insulin resistance / T2DM, a hallmark of Alström syndrome, ALMS1 is shown to be required for trafficking of the insulin receptor GLUT4 to the plasma membrane, adipogenesis, and regulation of pancreatic beta cell mass [Hearn 2019]. ALMS1 is widely expressed in a context-dependent manner: its expression level increases during terminal differentiation of neonatal mouse cardiomyocytes, and during primary cilium formation, but decreases as preadipocytes differentiate to mature adipocytes [Hearn 2019].

Mechanism of disease causation. Alström syndrome is caused by loss of function of ALMS1 protein. More than 200 ALMS1 pathogenic variants have been identified to date; almost all are nonsense or frameshift variants associated with complete lack of protein expression [Marshall et al 2015, Chen et al 2017].

ALMS1-specific laboratory technical considerations. The majority of ALMS1 variants are clustered in three large exons: exon 8 (which harbors almost half of the variants, consistent with its large size encompassing 49% of the coding sequence of the gene), exon 10, and exon 16 [Marshall et al 2015].

Given the clinical overlap between Alström syndrome and other ciliopathies, extreme caution should be exercised in classifying ALMS1 missense variants as pathogenic. A ciliopathy gene panel should be performed especially in individuals with mild/atypical Alström syndrome who have ALMS1 missense variants.

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Author History

Tim Barrett, MD (2019-present)
Catherine Carey, MD, FRCP; Torbay Hospital, Devon (2003-2019)
Tarekegn Geberhiwot, MD (2019-present)
Meral Gunay-Aygun, MD (2019-present)
Ian Hopkinson, BSc (Hons), MBChB, PhD, MRCGP; University College London (2003-2010)
Seamus Macdermott, MD, FRCS; Torbay Hospital, Devon (2003-2019)
Jan D Marshall, MS; The Jackson Library, Bar Harbor (2003-2016*)
Richard B Paisey, MD, FRCP (2005-present)
Rick Steeds, MD (2019-present)
Denise Williams, MD (2019-present)

*Author Jan Marshall died September 6, 2016.

Revision History

• 13 June 2019 (bp) Comprehensive update posted live
• 31 May 2012 (me) Comprehensive update posted live
• 8 June 2010 (me) Comprehensive update posted live
• 25 June 2007 (me) Comprehensive update posted live
• 7 February 2005 (me) Comprehensive update posted live
• 11 May 2004 (ih) Revision: test availability
• 7 February 2003 (me) Review posted live
• 6 June 2002 (ih) Original submission